Gene expression profiles for predicting the efficacy of the anticancer drug 5-fluorouracil in breast cancer.
ABSTRACT Chemotherapy is an important postsurgery adjuvant therapy in the treatment of breast cancer. However, because of the individual genotype differences of patients, the drug efficacy differs from person to person, even when the same chemotherapy drug is administered. The purpose of this research was to probe the gene expression profiles to predict the efficacy of 5-fluorouracil (5-FU), the common drug used in chemotherapy for various type of cancers, in Taiwanese breast cancer patients. Microarray analysis was conducted on the cancer cell line ZR-75-1 with and without 5-FU stimulation to identify the differentially expressed genes. The significant overexpressed gene groups were selected after bioinformatics software analysis to explore the molecular mechanism of 5-FU. Six strains of breast cancer cell line purchased from American Type Culture Collection were used to analyze the expression profiles of the above target gene groups. IL18, CCL28, CXCL2, SOD1, HRAS, FDXR, and CHI3L1 genes were significantly differentially expressed in 5-FU responder and nonresponder cell lines. The selected gene groups were validated with 20 strains of breast cancer primary cultures established previously in our laboratory. The experimental results demonstrated that FAM46A, IL18, CCL28, TNF, CXCL2, PLEKHA8, HRAS, FDXR, and CHI3L1 genes showed statistically significant differential expression between primary breast cancer culture cells that respond and nonrespond to 5-FU. Six genes, IL18, CCL28, CXCL2, HRAS, FDXR, and CHI3L1, showed significant differential expression pattern in both American Type Culture Collection and primary breast cancer cultured cells. The findings of this study may serve as basis for predicting the effectiveness of 5-FU on breast cancer.
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ABSTRACT: 5-Fluorouracil (5-FU) is a commonly used drug for the treatment of malignant cancers. However, approximately 80% of patients undergoing 5-FU treatment suffer from gastrointestinal mucositis. The aim of this report was to identify the drug target for the 5-FU-induced intestinal mucositis. 5-FU-induced intestinal mucositis was established by intraperitoneally administering mice with 100 mg/kg 5-FU. Network analysis of gene expression profile and bioluminescent imaging were applied to identify the critical molecule associated with 5-FU-induced mucositis. Our data showed that 5-FU induced inflammation in the small intestine, characterized by the increased intestinal wall thickness and crypt length, the decreased villus height, and the increased myeloperoxidase activity in tissues and proinflammatory cytokine production in sera. Network analysis of 5-FU-affected genes by transcriptomic tool showed that the expression of genes was regulated by nuclear factor-κB (NF-κB), and NF-κB was the central molecule in the 5-FU-regulated biological network. NF-κB activity was activated by 5-FU in the intestine, which was judged by in vivo bioluminescence imaging and immunohistochemical staining. However, 5-aminosalicylic acid (5-ASA) inhibited 5-FU-induced NF-κB activation and proinflammatory cytokine production. Moreover, 5-FU-induced histological changes were improved by 5-ASA. In conclusion, our findings suggested that NF-κB was the critical molecule associated with the pathogenesis of 5-FU-induced mucositis, and inhibition of NF-κB activity ameliorated the mucosal damage caused by 5-FU.PLoS ONE 01/2012; 7(3):e31808. · 3.53 Impact Factor